The overall objective of my laboratory is to define the biochemical mechanisms underlying gene regulation in the developing and mature islet 2 cell. In recent years, a greater emphasis has been placed on the role of covalent histone modifications in mammalian gene transcription, particularly how such modifications enable states of open or closed chromatin (euchromatin or heterochromatin, respectively) at specific genetic loci. The collective studies of several laboratories including our own have established that Pdx1, a master transcriptional regulator in the pancreas, controls gene expression in part through recruitment of cofactors that covalently modify histones. Dimethylated histone H3-Lys4 appears to be a crucial euchromatin marker in differentiating and mature islets. Therefore, in principle, many of the effects of Pdx1 on pancreas development and islet function could be explained by its recruitment of histone methylating cofactors. We have identified a remarkably islet-enriched cofactor, Set7/9, that appears to be responsible for dimethylated H3-Lys4 at many Pdx1 target genes. Our preliminary studies show that Set7/9 haploinsufficiency in the islet leads to impaired transcription of many Pdx1 targets and causes islet dysfunction and glucose intolerance, effectively phenocopying Pdx1 haploinsufficiency itself. Thus, the overarching hypothesis of this proposal is that Set7/9 is a chromatin-modifying cofactor that functions as an effector of Pdx1 action in the developing and mature islet. To test this hypothesis, we propose the following 3 specific aims: Aim 1: Determine the role of Set7/9 in directing islet cell fate and mass accrual during pancreas development. Aim 2: Determine the role of Set7/9 in the maintenance of normal islet function and glucose homeostasis. Aim 3: Determine how a transcriptional complex involving Set7/9 and Pdx1 regulates MafA gene transcription in the developing and mature 2 cell. We believe that the successful completion of these aims will identify both the role and mechanisms of a crucial chromatin-modifying cofactor in islet development and function. PUBLIC HEALTH RELEVANCE: Diabetes is a disorder of insulin-producing and insulin-responsive cells that afflicts 24 million Americans, and its incidence is rising at an alarming rate. The specific goal of this grant is to investigate how genes are regulated in insulin-producing cells. Overall, this project seeks to understand how insulin-producing cells are formed and how specific genes might be used to reprogram other cell types to become insulin-producing cells for individuals with diabetes.